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1.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
2.  Impact of hepatitis C virus co-infection on HIV patients before and after highly active antiretroviral therapy: an immunological and clinical chemistry observation, Addis Ababa, Ethiopia 
BMC Immunology  2013;14:23.
Background
Hepatitis C virus (HCV) is an RNA virus which has been known to cause acute and chronic necro-inflammatory disease of the liver. It is the leading cause of end-stage liver disease and hepatocellular carcinoma. HIV is known to have a negative impact on the natural disease outcome and immune response of HCV infection, whereas the reverse remains unclear. We evaluated the impact of HCV co-infection on recovery of CD4+ and CD8+ T-cells and liver enzyme levels before and after initiation of highly active antiretroviral therapy (HAART) in HIV/HCV co-infected patients.
Methods
A hospital-based, observational, prospective cohort study design was used for this study. Pre-antiretroviral treatment (Pre-ART) and under HAART HIV mono-infected and HCV/HIV co-infected individuals who are under regular follow-up were recruited for this study. 387 blood samples were collected from volunteer, known HIV positive Ethiopian patients and screened for HCV. Twenty five HCV/HIV co-infected patients were prospectively followed for four years. CD4+ and CD8+ T-cells and liver enzyme levels were determined annually for each of the participant.
Results
The prevalence of HCV/HIV co-infection in this study was 6.5%. Both HCV/HIV co-infected and HIV mono-infected under HAART groups showed CD4+ recovery (343 Vs 426; P < 0.004, OR = 4.97, 95% CI = 2.41 to 10.27) respectively; but, the recovery rate was higher in mono-infected (80 Vs 426) than co-infected group (148 Vs 343). The recovery and/or decline pattern of CD8+ T-cells was the same with that of CD4+. In 75% of co-infected groups, the mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were above the upper limit of normal reference range. Analyses restricted to individuals who initiated HAART and pre-ART showed similar results.
Conclusion
We found that CD4+ T-cell recovery was negatively affected by the presence of ongoing HCV replication in under HAART co-infected individuals and fast decline of CD4+ T-cells in pre-ART patients. It was also associated with increased ALT and AST enzyme levels in both HAART initiated and treatment naïve co-infected patients.
doi:10.1186/1471-2172-14-23
PMCID: PMC3663769  PMID: 23679118
Immunological; HCV/HIV co-infection; Pre-ART; HAART; CD4+; CD8+; GOT; GPT; Alkaline phosphatase
3.  Hepatitis C Virus Quasispecies in HIV-Infected Women: Role of Injecting Drug Use and Highly Active Antiretroviral Therapy (HAART) 
Hepatology (Baltimore, Md.)  2007;46(2):359-370.
Despite the high frequency of HCV and HIV coinfection, little is known about HCV quasispecies in HIV-positive patients. The current analysis included 236 HIV+/anti-HCV+ women enrolled in the Women’s Interagency HIV Study (WIHS). Hypervariable region 1 of the second envelope gene was analyzed by single-strand conformation polymorphism (SSCP). The relationship between the HCV quasispecies and clinical and demographic features were analyzed in multivariate models. Age over 40 years and high HCV RNA load were the only factors significantly associated with quasispecies complexity, assessed as the number of SSCP bands. High HIV and HCV plasma loads were associated with quasispecies stability over time, as reflected by stable SSCP band patterns. However, women who were actively injecting drugs were 3 times more likely to experience quasispecies changes than their noninjecting counterparts. No affect on HCV quasi-species dynamics was noted in relation to CD4 count or highly active antiretroviral therapy (HAART). Conclusion: among HIV/HCV coinfected patients, HCV quasispecies complexity and dynamics correlate more closely with HIV and HCV plasma loads than with CD4+ cell counts. Active drug use is associated with quasispecies changes probably due to repeated superinfections with new HCV strains. This needs to be considered when planning treatment and prevention strategies for HCV in coinfected individuals.
doi:10.1002/hep.21715
PMCID: PMC3508063  PMID: 17659581
4.  Rates and impact of hepatitis on human immunodeficiency virus infection in a large African cohort 
AIM: To determine the rates and impact of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections on response to long-term highly active antiretroviral therapy (HAART) in a large human immunodeficiency virus (HIV) population in Nigeria.
METHODS: HBV and HCV as well as HIV infections are endemic in sub Saharan Africa. This was a retrospective cohort study of 19 408 adults who were recruited between June 2004 and December 2010 in the AIDS Prevention Initiative in Nigeria in Nigeria programme at Jos University Teaching Hospital. Serological assays, including HBV surface antigen (HBsAg) and hepatitis C antibody were used to categorise hepatitis status of the patients. HBsAg was determined using enzyme immunoassay (EIA) (Monolisa HBsAg Ultra3; Bio-Rad). HCV antibody was tested using third generation EIA (DIA.PRO Diagnostic, Bioprobes srl, Milan, Italy). HIV RNA levels were measured using Roche COBAS Amplicor HIV-1 monitor test version 1.5 (Roche Diagnostics, GmbH, Mannheim, Germany) with a detection limit of 400 copies/mL. Flow cytometry was used to determine CD4+ cell count (Partec, GmbH Munster, Germany). Comparison of categorical and continuous variables were achieved using Pearson’s χ2 and Kruskal Wallis tests respectively, on MedCalc for Windows, version 9.5.0.0 (MedCalc Software, Mariakerke, Belgium).
RESULTS: With an overall hepatitis screening rate of over 90% for each virus; HBV, HCV and HBV/HCV were detected in 3162 (17.8%), 1983 (11.3%) and 453 (2.5%) HIV infected adults respectively. The rate of liver disease was low, but highest among HIV mono-infected patients (29, 0.11%), followed by HBV co-infected patients (15, 0.08%). Patients with HBV co-infection and triple infection had higher log10 HIV RNA loads (HBV: 4.6 copies/mL vs HIV only: 4.5 copies/mL, P < 0.0001) and more severe immune suppression (HBV: 645, 55.4%; HBV/HCV: 97, 56.7%) prior to initiation of HAART compared to HIV mono-infected patients (1852, 48.6%) (P < 0.0001). Of 3025 patients who were 4.4 years on HAART and whose CD4 cell counts results at baseline and end of follow up were available for analyses, CD4 increase was significantly lower in those with HBV co-infection (HBV: 144 cells/mm3; HBV/HCV: 105 cells/mm3) than in those with HCV co-infection (165 cells/mm3) and HIV mono-infection (150 cells/mm3) (P = 0.0008).
CONCLUSION: High rates of HBV and HCV infections were found in this HIV cohort. CD4 recovery was significantly diminished in patients with HBV co-infection.
doi:10.3748/wjg.v19.i10.1602
PMCID: PMC3602477  PMID: 23538773
Human immunodeficiency virus; Hepatitis B; Hepatitis C; Africa; Liver disease
5.  Kidney and liver organ transplantation in persons with human immunodeficiency virus 
Executive Summary
Objective
The objective of this analysis is to determine the effectiveness of solid organ transplantation in persons with end stage organ failure (ESOF) and human immunodeficiency virus (HIV+)
Clinical Need: Condition and Target Population
Patients with end stage organ failure who have been unresponsive to other forms of treatment eventually require solid organ transplantation. Similar to persons who are HIV negative (HIV−), persons living with HIV infection (HIV+) are at risk for ESOF from viral (e.g. hepatitis B and C) and non-viral aetiologies (e.g. coronary artery disease, diabetes, hepatocellular carcinoma). Additionally, HIV+ persons also incur risks of ESOF from HIV-associated nephropathy (HIVAN), accelerated liver damage from hepatitis C virus (HCV+), with which an estimated 30% of HIV positive (HIV+) persons are co-infected, and coronary artery disease secondary to antiretroviral therapy. Concerns that the need for post transplant immunosuppression and/or the interaction of immunosuppressive drugs with antiretroviral agents may accelerate the progression of HIV disease, as well as the risk of opportunistic infections post transplantation, have led to uncertainty regarding the overall benefit of transplantation among HIV+ patients. Moreover, the scarcity of donor organs and their use in a population where the clinical benefit of transplantation is uncertain has limited the availability of organ transplantation to persons living with ESOF and HIV.
With the development of highly active anti retroviral therapy (HAART), which has been available in Canada since 1997, there has been improved survival and health-related quality of life for persons living with HIV. HAART can suppress HIV replication, enhance immune function, and slow disease progression. HAART managed persons can now be expected to live longer than those in the pre-HAART era and as a result many will now experience ESOF well before they experience life-threatening conditions related to HIV infection. Given their improved prognosis and the burden of illness they may experience from ESOF, the benefit of solid organ transplantation for HIV+ patients needs to be reassessed.
Evidence-Based Analysis Methods
Research Questions
What are the effectiveness and cost effectiveness of solid organ transplantation in HIV+ persons with ESOF?
Literature Search
A literature search was performed on September 22, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1996 to September 22, 2009.
Inclusion Criteria
Systematic review with or without a Meta analysis, RCT, Non-RCT with controls
HIV+ population undergoing solid organ transplantation
HIV+ population managed with HAART therapy
Controls include persons undergoing solid organ transplantation who are i) HIV− ii) HCV+ mono-infected, and iii) HIV+ persons with ESOF not transplanted.
Studies that completed and reported results of a Kaplan-Meier Survival Curve analysis.
Studies with a minimum (mean or medium) follow up of 1-year.
English language citations
Exclusion Criteria
Case reports and case series were excluded form this review.
Outcomes of Interest
i) Risk of Death after transplantation
ii) Death censored graft survival (DCGS)
iii) HIV disease progression defined as the post transplant incidence of:
- opportunistic infections or neoplasms,
- CD4+ T-cell count < 200mm3, and
- any detectable level of plasma HIV viral load.
iv) Acute graft rejection,
v) Return to dialysis,
vi) Recurrence of HCV infection
Summary of Findings
No direct evidence comparing an HIV+ cohort undergoing transplantation with the same not undergoing transplantation (wait list) was found in the literature search.
The results of this review are reported for the following comparison cohorts undergoing transplantation:
i) Kidney Transplantation: HIV+ cohort compared with HIV− cohort
ii) Liver Transplantation: HIV+ cohort compared with HIV− negative cohort
iii) Liver Transplantation: HIV+ HCV+ (co-infected) cohort compared with HCV+ (mono-infected) cohort
Kidney Transplantation: HIV+ vs. HIV−
Based on a pooled HIV+ cohort sample size of 285 patients across four studies, the risk of death after kidney transplantation in an HIV+ cohort does not differ to that of an HIV− cohort [hazard ratio (HR): 0.90; 95% CI: 0.36, 2.23]. The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported in one study with an HIV+ cohort sample size of 100, and was statistically significantly different (p=.03) to that in the HIV− cohort (n=36,492). However, the quality of evidence supporting this outcome was determined to be very low. There was also uncertainty in the rate of return to dialysis after kidney transplantation in both the HIV+ and HIV− groups and the effect, if any, this may have on patient survival. Because of the very low quality evidence rating, the effect of kidney transplantation on HIV-disease progression is uncertain.
The rate of acute graft rejection was determined using the data from one study. There was a nonsignificant difference between the HIV+ and HIV− cohorts (OR 0.13; 95% CI: 0.01, 2.64), although again, because of very low quality evidence there is uncertainty in this estimate of effect.
Liver Transplantation: HIV+ vs. HIV−
Based on a combined HIV+ cohort sample size of 198 patient across five studies, the risk of death after liver transplantation in an HIV+ cohort (with at least 50% of the cohort co-infected with HCV+) is statistically significantly 64% greater compared with an HIV− cohort (HR: 1.64; 95% CI: 1.32, 2.02). The quality of evidence supporting this outcome is very low.
Death censored graft survival was reported for an HIV+ cohort in one study (n=11) however the DCGS rate of the contemporaneous control HIV− cohort was not reported. Because of sparse data the quality of evidence supporting this outcome is very low indicating death censored graft survival is uncertain.
Both the CD4+ T-cell count and HIV viral load appear controlled post transplant with an incidence of opportunistic infection of 20.5%. However, the quality of this evidence for these outcomes is very low indicating uncertainty in these effects. Similarly, because of very low quality evidence there is uncertainty in the rate of acute graft rejection among both the HIV+ and HIV− groups
Liver Transplantation: HIV+/HCV+ vs. HCV+
Based on a combined HIV+/HCV+ cohort sample size of 156 from seven studies, the risk of death after liver transplantation is significantly greater (2.8 fold) in a co-infected cohort compared with an HCV+ mono-infected cohort (HR: 2.81; 95% CI: 1.47, 5.37). The quality of evidence supporting this outcome is very low. Death censored graft survival evidence was not available.
Regarding disease progression, based on a combined sample size of 71 persons in the co-infected cohort, the CD4+ T-cell count and HIV viral load appear controlled post transplant; however, again the quality of evidence supporting this outcome is very low. The rate of opportunistic infection in the co-infected cohort was 7.2%. The quality of evidence supporting this estimate is very low, indicating uncertainty in these estimates of effect.
Based on a combined HIV+/HCV+ cohort (n=57) the rate of acute graft rejection does not differ to that of an HCV+ mono-infected cohort (OR: 0.88; 95% CI: 0.44, 1.76). Also based on a combined HIV+/HCV+ cohort (n=83), the rate of HCV+ recurrence does not differ to that of an HCV+ mono-infected cohort (OR: 0.66; 95% CI: 0.27, 1.59). In both cases, the quality of the supporting evidence was very low.
Overall, because of very low quality evidence there is uncertainty in the effect of kidney or liver transplantation in HIV+ persons with end stage organ failure compared with those not infected with HIV. Examining the economics of this issue, the cost of kidney and liver transplants in an HIV+ patient population are, on average, 56K and 147K per case, based on both Canadian and American experiences.
PMCID: PMC3377507  PMID: 23074407
6.  Effectiveness of HCV core antigen and RNA quantification in HCV-infected and HCV/HIV-1-coinfected patients 
BMC Infectious Diseases  2014;14(1):577.
Background
The measurement of hepatitis C virus core antigen (HCV-coreAg) has been shown to be an indicator of active HCV infection. The aim of the present study was 1) to investigate the stability and effectiveness of HCV-coreAg and HCV-RNA quantification in HCV infection with or without HIV-1 coinfection, 2) to explore the association between the HCV-coreAg/HCV-RNA (Ag/RNA) ratio and the immune status in chronic HCV/HIV-1-coinfected patients.
Methods
A longitudinal investigation comprised of 227 HCV-monoinfected (n = 129) and HCV/HIV-1-coinfected (n = 98) patients was initiated in August 2009, and 139 (73 with HCV monoinfection and 66 with HCV/HIV-1 coinfection) were followed up in August 2012. Both HCV core antigen and HCV RNA quantification were determined on this cryopreserved plasma. HCV core antigen and HCV RNA quantification were performed subsequently. In addition, an in vitro experiment investigating the possibility of degradation of HCV components (core antigen and RNA) were conducted.
Results
Significant and stable correlations (p < 0.001) were observed both in chronic HCV-monoinfected and HCV/HIV-1-coinfected patients over the 3-year observation. Coinfected patients with immunocompromised condition had a significantly higher (p < 0.05) Ag/RNA ratios than those patients with immunocompetent condition both at two time points (2009 and 2012). Moreover, the Ag/RNA ratios were negatively correlated with CD4+ T-cell counts (p < 0.001). An in vitro experiment investigated the possibility of the slower degradation of HCV particles under HIV-related immunocompromised condition was conducted and the data demonstrated that the Ag/RNA ratios were significantly higher in HIV-1-positive plasma than in healthy plasma (p = 0.005) in this study.
Conclusions
Our longitudinal study indicated that the HCV-coreAg presented comparable dynamics over time as HCV RNA in chronic HCV-infected patients. Meanwhile, the HCV-coreAg/HCV-RNA ratio was closely associated with immune status in HCV/HIV-1-coinfected patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0577-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0577-1
PMCID: PMC4225041  PMID: 25371245
CD4+ T-cell counts; Coinfection; HCV-coreAg; HCV-RNA; HCV/HIV-1; Ratio
7.  Interleukin 10 Responses Are Associated With Sustained CD4 T-Cell Counts in Treated HIV Infection 
The Journal of Infectious Diseases  2012;206(5):780-789.
Background.Inflammation persists in treated human immunodeficiency virus (HIV) infection and may contribute to an increased risk for non–AIDS-related pathologies. We investigated the correlation of cytokine responses with changes in CD4 T-cell levels and coinfection with hepatitis C virus (HCV) during highly active antiretroviral treatment (HAART).
Methods.A total of 383 participants in the Women's Interagency HIV Study (212 with HIV monoinfection, 56 with HCV monoinfection, and 115 with HIV/HCV coinfection) were studied. HIV-infected women had <1000 HIV RNA copies/mL, 99.7% had >200 CD4 T cells/μL; 98% were receiving HAART at baseline. Changes in CD4 T-cell count between baseline and 2–4 years later were calculated. Peripheral blood mononuclear cells (PBMCs) obtained at baseline were used to measure interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α) responses to Toll-like receptor (TLR) 3 and TLR4 stimulation.
Results.Undetectable HIV RNA (<80 copies/mL) at baseline and secretion of IL-10 by PBMCs were positively associated with gains in CD4 T-cell counts at follow-up. Inflammatory cytokines (IL-1β, IL-6, IL-12, and TNF-α) were also produced in TLR-stimulated cultures, but only IL-10 was significantly associated with sustained increases in CD4 T-cell levels. This association was significant only in women with HIV monoinfection, indicating that HCV coinfection is an important factor limiting gains in CD4 T-cell counts, possibly by contributing to unbalanced persistent inflammation.
Conclusions.Secreted IL-10 from PBMCs may balance the inflammatory environment of HIV, resulting in CD4 T-cell stability.
doi:10.1093/infdis/jis380
PMCID: PMC3491747  PMID: 22693231
8.  Quantification of hepatic FOXP3+ T‐lymphocytes in HIV/hepatitis C coinfection 
Journal of Viral Hepatitis  2013;21(4):251-259.
Summary
Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T‐regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.
doi:10.1111/jvh.12141
PMCID: PMC4159582  PMID: 24597693
coinfection; FOXP3 protein; hepacivirus; HIV; human; liver; regulatory; T‐lymphocytes
9.  Incident Hepatitis C Virus Infection among US HIV-Infected Men Enrolled in Clinical Trials 
HCV incidence from 1996-2008 among HIV-infected men in U.S. HIV therapeutic trials was 0.51 per 100 person-years. Incident HCV occurred primarily through non-parenteral means; 75% of seroconverters reported no drug injection. At-risk HIV-infected persons should have access to HCV surveillance
Background. Outbreaks of sexually transmitted hepatitis C virus (HCV) infection have been reported among human immunodeficiency virus (HIV)–infected men who have sex with men in Europe, Australia, and New York. Whether this is occurring across the United States is unknown.
Methods. We determined incidence of HCV infection during 1996–2008 among male participants of the AIDS Clinical Trial Group Longitudinal Linked Randomized Trials cohort, a long-term study of HIV-infected persons randomized into selected US-based clinical trials. We evaluated associations with self-reported injection drug use (IDU), time-varying CD4+ cell count, and HIV RNA level with use of multivariate Poisson regression. No sexual or non-IDU risk factor data was available.
Results. A total of 1830 men had an initial negative HCV antibody test result and at least 1 subsequent HCV antibody test result, contributing >7000 person-years. At the time of the initial negative HCV antibody test result, 94% of men were receiving highly active antiretroviral therapy (HAART) and 6% reported current or prior IDU. Thirty-six seroconverted, with overall incidence of .51 cases per 100 person-years (95% confidence interval, .36–.70). Mean age at seroconversion was 46 years. Seroconversion was associated with IDU (25% of seroconverters reported IDU history vs 5% of nonseroconverters; P < .001), whereas 75% (n = 27) of seroconverters reported no IDU (incidence, 2.67 cases per 100 person-years among IDUs, .40 cases per 100 person-years among non-IDUs). Seroconversion was associated with HIV RNA level >400 copies/mL (44% at time of antibody positivity vs 21% at time of last negative antibody test result; P = .02) but not with CD4+ cell count.
Conclusions. Incident HCV infection occurs in HIV-infected men involved in US HIV therapeutic trials, primarily through nonparenteral means, despite engagement in care and HAART. HCV antibody development was not related to immune status but was associated with inadequate HIV suppression. At-risk HIV-infected persons should have access to HCV surveillance.
doi:10.1093/cid/ciq201
PMCID: PMC3106260  PMID: 21282184
10.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
11.  Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon 
BMC Public Health  2010;10:105.
Background
Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon.
Methods
A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine.
Results
Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm3 (interquartile range [IQR] 67-218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 × 107 IU/mL for HBV (IQR 3680-1.59 × 108) and 928 000 IU/mL for HCV (IQR 178 400-2.06 × 106). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity.
Conclusion
This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown.
doi:10.1186/1471-2458-10-105
PMCID: PMC2841671  PMID: 20193053
12.  CD8+ T Cell Activation in Women Coinfected with Human Immunodeficiency Virus Type 1 and Hepatitis C Virus 
The Journal of infectious diseases  2008;197(10):1402-1407.
Immune activation is a hallmark of human immunodeficiency virus type 1 (HIV-1) infection and impacts innate and adaptive immunity. Individuals coinfected with HIV-1 and hepatitis C virus (HCV) may have increased immune activation early in HIV disease because of a high HCV antigen load in tissues such as the liver. We evaluated T cell markers of activation and maturation in women with or without HIV-1 infection, by HCV antibody and HCV RNA status. We found increased percentages of activated CD8+ T cells (i.e., CD8+HLA-DR+38+ cells and CD8+CD28+HLA-DR+ cells) but not of CD4+ T cells among women who tested positive for HIV-1, HCV antibody, and HCV RNA, compared with HIV-1–positive women who tested negative for HCV antibody. Because CD8+T cell activation is related to HIV-1 disease progression, these data may have implications for the medical management of patients coinfected with HIV-1 and HCV.
doi:10.1086/587696
PMCID: PMC2443164  PMID: 18444798
13.  Impact of Highly Active Antiretroviral Therapy and Immunologic Status on Hepatitis C Virus Quasispecies Diversity in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients 
Journal of Virology  2003;77(3):1940-1950.
This study analyzes the effect of highly active antiretroviral therapy (HAART), and thus immunologic status, on hepatitis C virus (HCV) load and quasispecies diversity in patients coinfected with the human immunodeficiency virus (HIV) and HCV. Three cohorts of coinfected patients were analyzed retrospectively over a period of 7 to 10 months: group A was antiretroviral drug naïve at baseline and then on HAART for the remainder of the study, group B did not receive antiretroviral therapy at any point, and group C was on HAART for the entire study. HCV quasispecies diversity was analyzed by sequencing hypervariable region 1. In a longitudinal analysis, there was no significant change from baseline in any immunologic, virologic, or quasispecies parameter in any of the three groups. However, in comparison to groups A and B, group C had significantly higher CD4+- and CD8+-cell counts, a trend toward a higher HCV load, and significantly increased number of HCV clones, entropy, genetic distance, and ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site (Ka/Ks). In addition, CD4+-cell count was positively correlated with HCV load, genetic distance, and Ka. Interestingly, patients infected with HCV genotype 2 or 3 had a significantly higher CD4+-cell count, HCV load, genetic distance, and Ka/Ks than those infected with genotype 1. These results suggest that there is no immediate effect of HAART on HCV but that, with prolonged HAART, immune restoration results in an increase in HCV load and quasispecies diversity.
doi:10.1128/JVI.77.3.1940-1950.2003
PMCID: PMC140862  PMID: 12525628
14.  Hepatitis C Viremia Is Associated with Cytomegalovirus IgG Antibody Levels in HIV-Infected Women 
PLoS ONE  2013;8(4):e61973.
Background
Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.
Methods
Associations of HCV with CMV seropositivity and CMV IgG levels were studied in 635 HIV-infected women, 187 of whom were HCV-seropositive, with adjustment in multivariable models for age, race/ethnicity, and HIV disease characteristics. Eighty one percent of the women reported receipt of highly active antiretroviral therapy (HAART) prior to or at CMV testing.
Results
In adjusted models women with chronic HCV had higher CMV IgG levels than those without HCV RNA (β = 2.86, 95% CI:0.89 – 4.83; P = 0.004). The association of HCV RNA with CMV IgG differed by age (Pinteraction = 0.0007), with a strong association observed among women in the low and middle age tertiles (≤45.3 years of age; β = 6.21, 95% CI:3.30 – 9.11, P<0.0001) but not among women in the high age tertile. CMV IgG levels were not associated with non-invasive measures of liver disease, APRI and FIB-4, or with HCV RNA level and adjustment for Epstein-Barr virus (EBV) IgG levels did not affect the association between HCV and CMV.
Conclusions
CMV IgG levels are higher in HCV/HIV co-infected women than in HIV mono-infected women. Further research on the association of HCV with CMV IgG is indicated because prior studies have found CMV IgG to be associated with morbidity and mortality in the general population and subclinical carotid artery disease in HIV-infected patients.
doi:10.1371/journal.pone.0061973
PMCID: PMC3629158  PMID: 23613990
15.  Presence of Hepatitis C Virus (HCV) RNA in the Genital Tracts of HCV/HIV-1–Coinfected Women 
The Journal of infectious diseases  2005;192(9):1557-1565.
Background
Hepatitis C virus (HCV)–infected women—in particular, those coinfected with human immunodeficiency virus type 1 (HIV-1)—can transmit infection to their children and sex partners.
Methods
The present study was conducted to analyze the presence of HCV RNA in cervicovaginal lavage (CVL) fluid from 71 women (58 HCV/HIV-1–coinfected women and 13 HCV-infected, HIV-1–uninfected women) enrolled in the Women’s Interagency HIV Study.
Results
HCV RNA was detected (by a commercial polymerase chain reaction assay) in CVL fluid from 18 (29%) of the HIV-1–infected women and from none of the HIV-1–uninfected women (P < .05). Multivariate analysis revealed that risk factors for the presence of HCV RNA in CVL fluid were HCV viremia (odds ratio [OR], 16.81; P = .02) and HIV-1 RNA in CVL fluid (OR, 19.87; P = .02). This observation suggests local interactions between HIV-1 and HCV in the genital tract compartment. There was no correlation between HCV RNA in CVL fluid and CD4, CD8, or CD3 cell counts, HIV-1 RNA viremia, the number of leukocytes in CVL fluid, or HIV-1 therapy. Furthermore, in 3 of 5 analyzed patients who had a detectable CVL HCV RNA load, we found viral variants differing in the 5′ untranslated region that were present neither in plasma nor in peripheral-blood mononuclear cells.
Conclusions
Our observations point to the importance of the genital tract compartment, in which local HCV replication could be facilitated by local HIV-1 replication.
doi:10.1086/491742
PMCID: PMC3164119  PMID: 16206070
16.  Monocyte Activation in HIV/HCV Coinfection Correlates with Cognitive Impairment 
PLoS ONE  2013;8(2):e55776.
Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects’ GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.
doi:10.1371/journal.pone.0055776
PMCID: PMC3578833  PMID: 23437063
17.  Clinicopathologic correlates of hepatitis C virus in brain: A pilot study 
Journal of neurovirology  2008;14(1):17-27.
Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase–polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naïve individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5′ untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naïve). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. We conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection.
doi:10.1080/13550280701708427
PMCID: PMC2729451  PMID: 18300072
brain; cognition; hepatitis C virus; HIV
18.  Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus 
The Journal of infectious diseases  2010;201(6):823-834.
Background
Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression.
Methods
Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated.
Results
HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P < .001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P < .001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8+CD38+DR+ T cells (hazard ratio, 2.94 [95% confidence interval, 1.50–5.77]; P =.001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80–4.35]; P =.16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8+CD38−DR+, CD4+CD38−DR−, and CD8+CD38−DR− T cells were associated with a >60% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women.
Conclusion
HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial.
doi:10.1086/650997
PMCID: PMC3105602  PMID: 20151840
19.  Selected biochemical and hematological abnormalities in Nigerians with human immunodeficiency virus and hepatitis C virus coinfection 
Background
Liver disease has emerged as a major cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection, now that antiretroviral therapy has become more effective and has prolonged life expectancy in HIV-infected patients. The main objectives of this study were to determine the prevalence of HIV/HCV coinfection and the pattern of hematological and biochemical abnormalities associated with such dual infection.
Methods
In this study, patients with HIV infection (cases) were tested for anti-HCV antibodies. There was a control group made up of apparently healthy individuals who came to hospital for medical examination for various reasons. They also had an anti-HCV antibody test. Those who tested positive for anti-HCV antibodies among the cases and control subjects were further evaluated for hemoglobin concentration, total white cell count, platelet count, and liver function.
Results
One hundred and eighty HIV-infected patients and 180 control subjects participated in the study. The seroprevalence of anti-HCV antibodies in the HIV-infected patients and control subjects were 6.7% and 4.4%, respectively (P = 0.57). Serum total bilirubin, conjugated bilirubin, and alkaline phosphatase were significantly higher in the HIV/HCV coinfected patients compared with their HCV monoinfected counterparts (P = 0.0396, 0.0001, and 0.0016, respectively). The mean hemoglobin, white cell count, platelet count, and CD4+ T lymphocyte count were significantly lower in the HIV/HCV coinfected patients than the HCV monoinfected control group (P = 0.0082, 0.0133, 0.0031, and 0.0001, respectively).
Conclusion
The seroprevalence of anti-HCV antibodies in HIV-infected Nigerian patients is 6.7%. Patients with HIV/HCV coinfection have lower blood counts, higher serum bilirubin, and higher serum alkaline phosphatase compared with patients having HCV monoinfection.
doi:10.2147/HMER.S21735
PMCID: PMC3846592  PMID: 24367222
human immunodeficiency virus; hepatitis C virus; coinfection; biochemical; hematological abnormalities
20.  Virological effectiveness and CD4+ T-cell increase over early and late courses in HIV infected patients on antiretroviral therapy: focus on HCV and anchor class received 
Background
The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART.
Methods
We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4–8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by ≥100/mm3 from baseline to month 4–8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome.
Results
The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining ≥100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up.
Conclusions
In this large cohort, HCV Ab reactivity was associated with an inferior virological outcome and an independent association between HCV Ab-positivity and smaller CD4+ increase was evident up to 12 months of follow-up. Although the difference in CD4+ T-cell count was modest, a stricter follow-up and optimization of HAART strategy appear to be important in HIV patients co-infected by HCV. Moreover, our data support anti-HCV treatment leading to HCV eradication as a means to facilitate the achievement of the viro-immunological goals of HAART.
doi:10.1186/1742-6405-9-18
PMCID: PMC3409064  PMID: 22703595
HIV; HCV; HAART
21.  Different HCV Genotype Distributions of HIV-Infected Individuals in Henan and Guangxi, China 
PLoS ONE  2012;7(11):e50343.
Background
Due to shared transmission routes, hepatitis C virus (HCV) infection is highly prevalent among people infected with human immunodeficiency virus (HIV). Highly active antiretroviral therapy (HAART) is associated with hepatotoxicity, leading to the negative effects on patients with HIV/HCV co-infection. In order to provide valuable information for HCV management in this particular population, we investigated the HCV genotypes in HIV-infected individuals from Henan and Guangxi, the two provinces with the most HIV-infected cases in China.
Methods
Individuals, who acquired HIV infection through various risk routes, were recruited from Henan and Guangxi. Test of antibodies against HCV (anti-HCV) was conducted, and detection of HCV RNA was performed by PCR amplification. HCV subtypes were determined by direct sequencing of amplicons, followed by phylogenetic analysis.
Results
We recruited a total of 1,112 HIV-infected people in this present study. Anti-HCV was detected from 218 (50.1%) patients from Henan and 81 (12.0%) patients from Guangxi, respectively. The highest prevalence of HIV/HCV co-infection was observed from FBDs (former blood donors) (87.2%) in Henan and IDUs (intravenous drug users) (81.8%) in Guangxi, respectively. The seroprevalence rate of HCV among people with sexual contact was significantly higher in Henan than in Guangxi (18.7% vs. 3.5%, P<0.05). The positive rate of HCV RNA in Henan and Guangxi was 30.6% (133/435) and 11.2% (76/677), respectively. Moreover, we found that 20 anti-HCV negative samples were HCV positive by PCR amplification. HCV subtype 1b (52.7%) was predominant in Henan, followed by subtype 2a (41.9%). The most frequently detected subtypes in Guangxi were 6a (35.6%) and 3b (32.9%).
Conclusion
The HCV genotype distributions were different in HIV-infected people from Henan and Guangxi. HIV/HCV co-infection was not only linked to the transmission routes, but also associated with the geographic position.
doi:10.1371/journal.pone.0050343
PMCID: PMC3511438  PMID: 23226265
22.  Diminished frequency of hepatitis C virus specific interferon γ secreting CD4+ T cells in human immunodeficiency virus/hepatitis C virus coinfected patients 
Gut  2006;55(10):1484-1487.
Background
Human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfection is a common and complex clinical problem in which loss of immunological control of HCV occurs, with increased HCV viral load and more aggressive liver disease. Cellular immune responses, particularly secretion of interferon γ (IFN‐γ) appear to be important in the control of HCV, and a detectable HCV specific CD4 response is associated with clearance of the virus. HCV specific CD8+ T cell responses, weak in chronic HCV infection, have been shown to be further impaired in HIV coinfection and this CD8+ T cell deficiency is related to the decline in CD4 T cell count.
Aims
To compare the CD4 T cell response to HCV in HIV/HCV coinfected and HCV monoinfected individuals and to determine the relationship of responses with declining CD4 count.
Patients
The study subjects were a cohort of 68 HCV monoinfected and 67 HCV/HIV coinfected haemophiliac children and adolescents (the Hemophilia Growth and Development Study) who were followed for a seven year period.
Methods
We analysed IFN‐γ secreting CD4+ responses to HCV proteins and peptides and HIV p24 antigen using an ELISpot assay.
Results
We found a significant decrease in HCV specific responses among those who were HIV coinfected (10/67 v 36/68; p<0.0001) both in numbers of responders and frequency of specific cells. This did not appear to be closely related to CD4 count.
Conclusions
The reduction in HCV specific CD4 T cells in coinfection provide a cellular mechanism for the loss of control of HCV in coinfected individuals, even in those with relatively preserved CD4+ T cell counts and CD4+ T cell responses to HIV.
doi:10.1136/gut.2005.083758
PMCID: PMC1629042  PMID: 16543291
hepatitis C virus; human immunodeficiency virus; CD4+ T cells; coinfection
23.  Dynamic analysis of Th1/Th2 cytokine concentration during antiretroviral therapy of HIV-1/HCV co-infected Patients 
BMC Infectious Diseases  2012;12:102.
Background
Co-infection with hepatitis C (HCV) is very common in human immunodeficiency virus 1 (HIV-1) infected patients. Although HIV co-infection clearly accelerates progression of HCV-related fibrosis and liver disease, controversy remains as to the impact of HCV on HIV disease progression in co-infected patients. HIV can cause immune dysfunction, in which the regulatory function of T helper (Th) cells is very essential. Moreover, cytokines derived from Th cells play a prominent role in viral infection. Investigating the functional changes of Th1 and Th2 cells in cytokine level can improve the understanding of the effect of co-infected HCV on HIV infection.
Methods
In this study, we measured the baseline Th1/Th2 cytokine concentration in sera by using flow cytometry in HIV/HCV co-infection, HIV mono-infection, HCV mono-infection, and healthy control group, as well as the dynamic changes of these cytokine levels after receiving highly active antiretroviral therapy (HAART).
Results
The ratio of Th1 and Th2 cytokine concentration in HIV/HCV co-infection was higher than HCV mono-infection and healthy control group, while lower than HIV mono-infection group. After HAART was initiated, the Th1/Th2 ratio of HIV/HCV co-infection group decreased to the same level of healthy control, while HIV mono-infection group was still higher than the control group.
Conclusions
There was no significant evidence showing co-infected with HCV had negative effect on HIV related diseases. However, co-infected with HCV can decrease Th1/Th2 ratio by affecting Th1 cytokine level, especially the secretion of IFN-γ. With the initiation of HAART, Th1 and Th2 cytokine levels were progressively reduced. HIV was the main stimulating factor of T cells in HIV/HCV co-infection group.
doi:10.1186/1471-2334-12-102
PMCID: PMC3353863  PMID: 22533731
24.  Seroprevalence of Hepatitis B and C Viruses Among Children in Kilimanjaro Region, Tanzania 
Background
Data on human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection among children in Africa are limited. We evaluated the seroprevalence of both viruses among healthy, HIV-uninfected children and HIV-infected children in the Kilimanjaro region of northern Tanzania.
Methods
HBV and HCV markers were assessed using serum and plasma samples from HIV-negative children ages 1 month to 18 years, recruited primarily from 2 hospital vaccination clinics; and HIV-infected children 1–16 years of age, enrolled in care and on highly active antiretroviral therapy (HAART). HBV markers included hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (HBcAb). Evidence of any prior HBV infection was defined as a single positive HBsAg or HBcAb result; presumed chronic hepatitis B infection was defined as a single positive HBsAg result. HCV infection was assessed by anti-HCV enzyme-linked immunosorbent assay.
Results
Samples from 547 children were tested. Of 157 children infected with HIV, 9.6% (95% CI: 4.9, 14.2) showed evidence of any HBV infection, compared to 2.1% (95% CI: .6, 3.5) of HIV-negative children. Children with HIV were much more likely to show evidence of HBV infection than children without HIV (odds ratio [OR] = 5.0, P < .0001). Prevalence of presumed chronic HBV infection was 2.9% (95% CI: 1.5, 4.3) overall. Again, prevalence was higher among HIV-infected children (7.0% [95% CI: 3.0, 11.0]) compared to HIV-negative children (1.3% [95% CI: .2, 2.4]; OR = 5.8 [P = .0003]). Of 546 samples tested for anti-HCV antibody, none were positive.
Conclusion
HBV seroprevalence is high among children in the Kilimanjaro Region, with a significantly higher prevalence among children who are infected with HIV. Routine screening for HBV is needed among HIV-infected children. Patients with coinfection require closer monitoring of liver transaminases due to potential for hepatic toxicities, and they may need HAART regimens that will target both viruses. Guidelines for the management of coinfected children are urgently needed.
doi:10.1093/jpids/pit018
PMCID: PMC3869471  PMID: 24363930
HIV; Hepatitis B; Hepatitis C; Children; Sub-Saharan Africa
25.  Cost of human immunodeficiency virus infection in Italy, 2007–2009: effective and expensive, are the new drugs worthwhile? 
Background
In recent years, the increased efficacy and effectiveness of antiretroviral treatment has led to longer survival of patients infected with human immunodeficiency virus (HIV), but has also raised the question of what happens to consumption of resources. Early highly active antiretroviral treatment (HAART), management of hepatitis C virus (HCV) coinfection, and expensive newly marketed drugs may affect the economic sustainability of treatment from the point of view of the National Healthcare Services. The present study aimed to provide information on the economic burden of HIV-positive patients resident in the Lombardy region using a three-year time horizon.
Methods
This was a retrospective, observational, budget impact study, based on information collected for the period 2007–2009, including hospitalizations, outpatient services, and HAART and non-HAART drug utilization. Patients with confirmed HIV infection, aged ≥ 18 years, resident in the Lombardy region, and followed at the “L Sacco” Hospital in Milan from 2007 to 2009 were eligible.
Results
A total of 483 patients (mean age 44.1 years) were included in the study. The mean CD4+ cell count increased over the study period from 462 ± 242 cells/mm3 in 2007, to 513 ± 267 cells/mm3 in 2008, to 547 ± 262 cells/mm3 in 2009. In total, 162 subjects (33.5%) were coinfected with HCV. Hospitalizations and HAART costs increased from 2007 to 2009, whereas outpatient visits and non-HAART drug costs decreased slightly over time. The total cost increase was also significant when limiting the analysis to experienced patients, HCV-negative patients, and experienced HCV-negative patients.
Conclusion
CD4+ cell count, a major predictor of costs, increased over the study period. However, immunological improvement was achieved by greater expense in the short term. Whether this may be compensated by a long-term decrease in opportunistic infections and in the costs of management of HIV-related events is an area still to be investigated.
doi:10.2147/CEOR.S35194
PMCID: PMC3439221  PMID: 22973114
health care costs; human immunodeficiency virus infection; risk factors; retrospective study

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